Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL

Abstract

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Graphical abstract

Figure 1.

Antigen expression in major molecular subgroups. Unsupervised hierarchical clustering of antigen expression in each of 413 E2993 patients. The patient cohort consists of 244 samples from E2993 patients who were BCR-ABL1⁻ and were genotyped (excluding molecular subgroups with <5 patients and B-other) and 169 E2993 patients with BCR-ABL1 ALL. This approach identified characteristic antigen expression profiles within each of the 13 molecular subtypes, shown as black bars above the heatmap. Columns represent patients, and rows are antigens. Antigens are listed to the right of the heatmap. Expression levels reflect the percentage of antibody-binding leukemic lymphoblasts, except for CD38_mfi, which reflects intensity of antigen expression. High expression and low expression of antigens in the heatmap are shown in shades of red and blue, respectively. The first row above the heatmap aligns genotypes with B-lineage maturation stages. ZNF384-R includes ZNF384-like; ETV6-RUNX1 includes ETV6-RUNX1-like; KMT2A-R includes patients who were both KMT2A-AFF1 and KMT2A–non-AFF1; low_hypo, LH and NH; mcd22, membrane (surface) CD22.

Figure 2.

OS of patients with BCR/ABL1⁻ B-ALL on UKALLXII/E2993 by matched sibling donor availability at 10 years. Kaplan-Meier estimate of OS for patients who are BCR/ABL1-negative B-ALL on UKALLXII/E2993 by availability of a matched donor at 10 years of follow-up.

Figure 3.

Outcome of E2993 molecular subgroups. Kaplan-Meier estimates for RFS and OS of molecular subgroups included in the outcome analysis. The RFS analysis included only patients who achieved a complete remission (DUX4-R, 18 patients; TCF3-PBX1, 12; PAX5 P80R, 9; Hyperdiploid, 15; ETV6-RUNX1/-like, 5; ZNF384-R/-like, 10; PAX5alt, 24; MEF2D-R, 6; KMT2A-AFF1, 21; Ph-like, 41; Hypodiploid/Haploid, 24; BCL2/MYC, 3). The OS analysis included all patients with outcome information (DUX4-R, 20 patients; TCF3-PBX1, 15; PAX5 P80R, 9; Hyperdiploid, 15; ETV6-RUNX1/-like, 5; ZNF384-R/-like, 11; PAX5alt, 27; MEF2D-R, 6; KMT2A-AFF1, 26; Ph-like, 46; Hypodiploid/Haploid, 31; BCL2/MYC, 6). Among DUX4-R, ETV6-RUNX1/-like, TCF3-PBX1, PAX5 P80R, and hyperdiploid patients, neither RFS nor OS varied significantly.

Figure 4.

Outcome of E2993 patients by protocol-defined and molecular-defined risk assignment. Kaplan-Meier estimates of RFS and OS for patients stratified by their protocol-defined risk: low risk (pLR) and high risk (pHR), and molecular risk: mSR, mIR, and mHR.